Individual deviations from normative models of brain structure in a large cross-sectional schizophrenia cohort.

The heterogeneity of schizophrenia has defied efforts to derive reproducible and definitive anatomical maps of structural brain changes associated with the disorder. We aimed to map deviations from normative ranges of brain structure for individual patients and evaluate whether the loci of individual deviations recapitulated group-average brain maps of schizophrenia pathology. For each of 48 white matter tracts and 68 cortical regions, normative percentiles of variation in fractional anisotropy (FA) and cortical thickness (CT) were established using diffusion-weighted and structural MRI from healthy adults (n = 195). Individuals with schizophrenia (n = 322) were classified as either within the normative range for healthy individuals of the same age and sex (5-95% percentiles), infra-normal (<5% percentile) or supra-normal (>95% percentile). Repeating this classification for each tract and region yielded a deviation map for each individual. Compared to the healthy comparison group, the schizophrenia group showed widespread reductions in FA and CT, involving virtually all white matter tracts and cortical regions. Paradoxically, however, no more than 15-20% of patients deviated from the normative range for any single tract or region. Furthermore, 79% of patients showed infra-normal deviations for at least one locus (healthy individuals: 59 ± 2%, p < 0.001). Thus, while infra-normal deviations were common among patients, their anatomical loci were highly inconsistent between individuals. Higher polygenic risk for schizophrenia associated with a greater number of regions with infra-normal deviations in CT (r = -0.17, p = 0.006). We conclude that anatomical loci of schizophrenia-related changes are highly heterogeneous across individuals to the extent that group-consensus pathological maps are not representative of most individual patients. Normative modeling can aid in parsing schizophrenia heterogeneity and guiding personalized interventions.

Personalized connectivity-guided DLPFC-TMS for depression: Advancing computational feasibility, precision and reproducibility.

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) is an established treatment for refractory depression, however, therapeutic outcomes vary. Mounting evidence suggests that clinical response relates to functional connectivity with the subgenual cingulate cortex (SGC) at the precise DLPFC stimulation site. Critically, SGC-related network architecture shows considerable interindividual variation across the spatial extent of the DLPFC, indicating that connectivity-based target personalization could potentially be necessary to improve treatment outcomes. However, to date accurate personalization has not appeared feasible, with recent work indicating that the intraindividual reproducibility of optimal targets is limited to 3.5 cm. Here we developed reliable and accurate methodologies to compute individualized connectivity-guided stimulation targets. In resting-state functional MRI scans acquired across 1,000 healthy adults, we demonstrate that, using this approach, personalized targets can be reliably and robustly pinpointed, with a median accuracy of ~2 mm between scans repeated across separate days. These targets remained highly stable, even after 1 year, with a median intraindividual distance between coordinates of only 2.7 mm. Interindividual spatial variation in personalized targets exceeded intraindividual variation by a factor of up to 6.85, suggesting that personalized targets did not trivially converge to a group-average site. Moreover, personalized targets were heritable, suggesting that connectivity-guided rTMS personalization is stable over time and under genetic control. This computational framework provides capacity for personalized connectivity-guided TMS targets to be robustly computed with high precision and has the flexibly to advance research in other basic research and clinical applications.

A multivariate neuroimaging biomarker of individual outcome to transcranial magnetic stimulation in depression.

The neurobiology of major depressive disorder (MDD) remains incompletely understood, and many individuals fail to respond to standard treatments. Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) has emerged as a promising antidepressant therapy. However, the heterogeneity of response underscores a pressing need for biomarkers of treatment outcome. We acquired resting state functional magnetic resonance imaging (rsfMRI) data in 47 MDD individuals prior to 5-8 weeks of rTMS treatment targeted using the F3 beam approach and in 29 healthy comparison subjects. The caudate, prefrontal cortex, and thalamus showed significantly lower blood oxygenation level-dependent (BOLD) signal power in MDD individuals at baseline. Critically, individuals who responded best to treatment were associated with lower pre-treatment BOLD power in these regions. Additionally, functional connectivity (FC) in the default mode and affective networks was associated with treatment response. We leveraged these findings to train support vector machines (SVMs) to predict individual treatment responses, based on learned patterns of baseline FC, BOLD signal power and clinical features. Treatment response (responder vs. nonresponder) was predicted with 85-95% accuracy. Reduction in symptoms was predicted to within a mean error of ±16% (r = .68, p < .001). These preliminary findings suggest that therapeutic outcome to DLPFC-rTMS could be predicted at a clinically meaningful level using only a small number of core neurobiological features of MDD, warranting prospective testing to ascertain generalizability. This provides a novel, transparent and physiologically plausible multivariate approach for classification of individual response to what has become the most commonly employed rTMS treatment worldwide. This study utilizes data from a larger clinical study (Australian New Zealand Clinical Trials Registry: Investigating Predictors of Response to Transcranial Magnetic Stimulation for the Treatment of Depression; ACTRN12610001071011; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=336262).

The effects of individualised intermittent theta burst stimulation in the prefrontal cortex: A TMS-EEG study.

Recent studies have highlighted variability in response to theta burst stimulation (TBS) in humans. TBS paradigm was originally developed in rodents to mimic gamma bursts coupled with theta rhythms, and was shown to elicit long-term potentiation. The protocol was subsequently adapted for humans using standardised frequencies of stimulation. However, each individual has different rhythmic firing pattern. The present study sought to explore whether individualised intermittent TBS (Ind iTBS) could outperform the effects of two other iTBS variants. Twenty healthy volunteers received iTBS over left prefrontal cortex using 30 Hz at 6 Hz, 50 Hz at 5 Hz, or individualised frequency in separate sessions. Ind iTBS was determined using theta-gamma coupling during the 3-back task. Concurrent use of transcranial magnetic stimulation and electroencephalography (TMS-EEG) was used to track changes in cortical plasticity. We also utilised mood ratings using a visual analogue scale and assessed working memory via the 3-back task before and after stimulation. No group-level effect was observed following either 30 or 50 Hz iTBS in TMS-EEG. Ind iTBS significantly increased the amplitude of the TMS-evoked P60, and decreased N100 and P200 amplitudes. A significant positive correlation between neurophysiological change and change in mood rating was also observed. Improved accuracy in the 3-back task was observed following both 50 Hz and Ind iTBS conditions. These findings highlight the critical importance of frequency in the parameter space of iTBS. Tailored stimulation parameters appear more efficacious than standard paradigms in neurophysiological and mood changes. This novel approach presents a promising option and benefits may extend to clinical applications.

GABA concentration in sensorimotor cortex following high-intensity exercise and relationship to lactate levels.

KEY POINTS: Magnetic resonance spectroscopy was conducted before and after high-intensity interval exercise. Sensorimotor cortex GABA concentration increased by 20%. The increase was positively correlated with the increase in blood lactate. There was no change in dorsolateral prefrontal cortex. There were no changes in the glutamate-glutamine-glutathione peak. ABSTRACT: High-intensity exercise increases the concentration of circulating lactate. Cortical uptake of blood borne lactate increases during and after exercise; however, the potential relationship with changes in the concentration of neurometabolites remains unclear. Although changes in neurometabolite concentration have previously been demonstrated in primary visual cortex after exercise, it remains unknown whether these changes extend to regions such as the sensorimotor cortex (SM) or executive regions such as the dorsolateral prefrontal cortex (DLPFC). In the present study, we explored the acute after-effects of high-intensity interval training (HIIT) on the concentration of gamma-Aminobutyric acid (GABA) and the combined glutamate-glutamine-glutathione (Glx) spectral peak in the SM and DLPFC, as well as the relationship with blood lactate levels. Following HIIT, there was a robust increase in GABA concentration in the SM, as evident across the majority of participants. This change was not observed in the DLPFC. Furthermore, the increase in SM GABA was positively correlated with an increase in blood lactate. There were no changes in Glx concentration in either region. The observed increase in SM GABA concentration implies functional relevance, whereas the correlation with lactate levels may relate to the metabolic fate of exercise-derived lactate that crosses the blood-brain barrier.

Impact of different intensities of intermittent theta burst stimulation on the cortical properties during TMS-EEG and working memory performance.

Intermittent theta burst stimulation (iTBS) is a noninvasive brain stimulation technique capable of increasing cortical excitability beyond the stimulation period. Due to the rapid induction of modulatory effects, prefrontal application of iTBS is gaining popularity as a therapeutic tool for psychiatric disorders such as depression. In an attempt to increase efficacy, higher than conventional intensities are currently being applied. The assumption that this increases neuromodulatory may be mechanistically false for iTBS. This study examined the influence of intensity on the neurophysiological and behavioural effects of iTBS in the prefrontal cortex. Sixteen healthy participants received iTBS over prefrontal cortex at either 50, 75 or 100% resting motor threshold in separate sessions. Single-pulse TMS and concurrent electroencephalography (EEG) was used to assess changes in cortical reactivity measured as TMS-evoked potentials and oscillations. The n-back task was used to assess changes in working memory performance. The data can be summarised as an inverse U-shape relationship between intensity and iTBS plastic effects, where 75% iTBS yielded the largest neurophysiological changes. Improvement in reaction time in the 3-back task was supported by the change in alpha power, however, comparison between conditions revealed no significant differences. The assumption that higher intensity results in greater neuromodulatory effects may be false, at least in healthy individuals, and should be carefully considered for clinical populations. Neurophysiological changes associated with working memory following iTBS suggest functional relevance. However, the effects of different intensities on behavioural performance remain elusive in the present healthy sample.

Impaired neuroplasticity in the prefrontal cortex in depression indexed through paired associative stimulation.

BACKGROUND: Dysfunctional neuroplasticity may be one of the pathophysiological mechanisms underlying major depression. We have previously established methods to assess neuroplasticity from the dorsolateral prefrontal cortex (DLPFC) using a paired associative stimulation (PAS) paradigm, which pairs a preceding peripheral nerve stimulation with subsequent transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG). We aimed to investigate neuroplasticity through the PAS paradigm in the DLPFC in patients with depression compared to healthy subjects. METHODS: Twenty-nine patients with depression and 28 healthy controls participated in this study. There were no significant age or sex differences between the two groups. All participants received PAS paradigm in the DLPFC. We analyzed PAS induced potentiation from the DLPFC in both groups calculating the power of TMS-evoked potentials (TEP). A two-way ANOVA with PAS effect as a within-subject factor and diagnostic group as a between-subject factor was performed to examine the group differences in the PAS paradigm. RESULTS: DLPFC-PAS induced a significant potentiation at the stimulation site in both patients and healthy subjects (mean ± SD: 1.24 ± 0.33 [µV] vs. 1.48 ± 0.28 [µV]). However, when we compared PAS potentiation between patients and healthy subjects, there were significant main effects of PAS (F1,53  = 68.63, p < 0.0001) and PAS-by-diagnostic group interaction (F1,53  = 25.05, p < 0.0001). Post hoc analysis demonstrated that patients had a significantly lower PAS potentiation compared to healthy subjects (t55  = 3.128, p = 0.003). CONCLUSTIONS: Our findings provide evidence for impaired neuroplasticity in DLPFC in patients with depression compared to healthy subjects. Such findings may ultimately help us understand the pathophysiology of MDD and mechanisms involved in its treatment.

Augmenting Plasticity Induction in Human Motor Cortex by Disinhibition Stimulation.

Cellular studies showed that disinhibition, evoked pharmacologically or by a suitably timed priming stimulus, can augment long-term plasticity (LTP) induction. We demonstrated previously that transcranial magnetic stimulation evokes a period of presumably GABA(B)ergic late cortical disinhibition (LCD) in human primary motor cortex (M1). Here, we hypothesized that, in keeping with cellular studies, LCD can augment LTP-like plasticity in humans. In Experiment 1, patterned repetitive TMS was applied to left M1, consisting of 6 trains (intertrain interval, 8 s) of 4 doublets (interpulse interval equal to individual peak I-wave facilitation, 1.3-1.5 ms) spaced by the individual peak LCD (interdoublet interval (IDI), 200-250 ms). This intervention (total of 48 pulses applied over ∼45 s) increased motor-evoked potential amplitude, a marker of corticospinal excitability, in a right hand muscle by 147% ± 4%. Control experiments showed that IDIs shorter or longer than LCD did not result in LTP-like plasticity. Experiment 2 indicated topographic specificity to the M1 hand region stimulated by TMS and duration of the LTP-like plasticity of 60 min. In conclusion, GABA(B)ergic LCD offers a powerful new approach for augmenting LTP-like plasticity induction in human cortex. We refer to this protocol as disinhibition stimulation (DIS).

A combined TMS-EEG study of short-latency afferent inhibition in the motor and dorsolateral prefrontal cortex.

Combined transcranial magnetic stimulation and electroencephalography (TMS-EEG) enables noninvasive neurophysiological investigation of the human cortex. A TMS paradigm of short-latency afferent inhibition (SAI) is characterized by attenuation of the motor-evoked potential (MEP) and modulation of N100 of the TMS-evoked potential (TEP) when TMS is delivered to motor cortex (M1) following median nerve stimulation. SAI is a marker of cholinergic activity in the motor cortex; however, the SAI has not been tested from the prefrontal cortex. We aimed to explore the effect of SAI in dorsolateral prefrontal cortex (DLPFC). SAI was examined in 12 healthy subjects with median nerve stimulation and TMS delivered to M1 and DLPFC at interstimulus intervals (ISIs) relative to the individual N20 latency. SAI in M1 was tested at the optimal ISI of N20 + 2 ms. SAI in DLPFC was investigated at a range of ISI from N20 + 2 to N20 + 20 ms to explore its temporal profile. For SAI in M1, the attenuation of MEP amplitude was correlated with an increase of TEP N100 from the left central area. A similar spatiotemporal neural signature of SAI in DLPFC was observed with a marked increase of N100 amplitude. SAI in DLPFC was maximal at ISI N20 + 4 ms at the left frontal area. These findings establish the neural signature of SAI in DLPFC. Future studies could explore whether DLPFC-SAI is neurophysiological marker of cholinergic dysfunction in cognitive disorders.

Heterosynaptic modulation of motor cortical plasticity in human.

Inductions of long-term potentiation (LTP) and depression (LTD) are modulated if they are preceded by a priming protocol, in a manner consistent with metaplasticity. Depotentiation refers to reversal of LTP by a subsequent protocol that has no effect by itself. Paired associative stimulation (PAS) at interstimulus interval of 25 ms (PAS25) and 10 ms (PAS10) produces spike timing-dependent LTP-like and LTD-like effects in human primary motor cortex. Continuous theta burst stimulation (cTBS) with 600 pulses produces an LTD-like effect, whereas cTBS with 150 pulses (cTBS150) has no effect by itself. We investigated whether cortical plasticity induced by PAS can be modulated by heterosynaptic inputs of cTBS150. PAS25 and PAS10 primed and followed by cTBS150 were compared withPAS25 and PAS10 alone. Motor evoked potential (MEP) amplitude, recruitment curve, and intracortical circuits including short-interval intracortical inhibition (SICI), long-interval intracortical inhibition (LICI), intracortical facilitation, and short-latency afferent inhibition were measured before and after the interventions. After PAS25 alone, MEP amplitude increased while intracortical circuits did not change. A priming cTBS150 enhanced the effects of PAS25 with further increase in MEP amplitude and led to reduction in SICI and LICI. PAS25 followed by cTBS150 led to reduced MEP amplitude and increased LICI and SICI. Both priming and following cTBS150 reversed the LTD-like effect produced by PAS10 with little change in intracortical circuits. We conclude that cortical plasticity induced by PAS and cTBS interacts in a heterosynaptic and bidirectional manner. The order of the interventions determines whether the underlying mechanisms are related to metaplasticity or depotentiation.

The influence of sensory afferent input on local motor cortical excitatory circuitry in humans.

In human, sensorimotor integration can be investigated by combining sensory input and transcranial magnetic stimulation (TMS). Short latency afferent inhibition (SAI) refers to motor cortical inhibition 20-25 ms after median nerve stimulation. We investigated the interaction between SAI and short-interval intracortical facilitation (SICF), an excitatory motor cortical circuit. Seven experiments were performed. Contrary to expectations, SICF was facilitated in the presence of SAI (SICF(SAI)). This effect is specific to SICF since there was no effect at SICF trough 1 when SICF was absent. Furthermore, the facilitatory SICF(SAI) interaction increased with stronger SICF or SAI. SAI and SICF correlated between individuals, and this relationship was maintained when SICF was delivered in the presence of SAI, suggesting an intrinsic relationship between SAI and SICF in sensorimotor integration. The interaction was present at rest and during muscle contraction, had a broad degree of somatotopic influence and was present in different interneuronal SICF circuits induced by posterior-anterior and anterior-posterior current directions. Our results are compatible with the finding that projections from sensory to motor cortex terminate in both superficial layers where late indirect (I-) waves are thought to originate, as well as deeper layers with more direct effect on pyramidal output. This interaction is likely to be relevant to sensorimotor integration and motor control.

Personalized and Circuit-Based Transcranial Magnetic Stimulation: Evidence, Controversies, and Opportunities.

The development of neuroimaging methodologies to map brain connectivity has transformed our understanding of psychiatric disorders, the distributed effects of brain stimulation, and how transcranial magnetic stimulation can be best employed to target and ameliorate psychiatric symptoms. In parallel, neuroimaging research has revealed that higher-order brain regions such as the prefrontal cortex, which represent the most common therapeutic brain stimulation targets for psychiatric disorders, show some of the highest levels of interindividual variation in brain connectivity. These findings provide the rationale for personalized target site selection based on person-specific brain network architecture. Recent advances have made it possible to determine reproducible personalized targets with millimeter precision in clinically tractable acquisition times. These advances enable the potential advantages of spatially personalized transcranial magnetic stimulation targeting to be evaluated and translated to basic and clinical applications. In this review, we outline the motivation for target site personalization, preliminary support (mostly in depression), convergent evidence from other brain stimulation modalities, and generalizability beyond depression and the prefrontal cortex. We end by detailing methodological recommendations, controversies, and notable alternatives. Overall, while this research area appears highly promising, the value of personalized targeting remains unclear, and dedicated large prospective randomized clinical trials using validated methodology are critical.

Characterizing the opioidergic mechanisms of repetitive transcranial magnetic stimulation-induced analgesia: a randomized controlled trial.

ABSTRACT: Repetitive transcranial magnetic stimulation (rTMS) is a promising technology to reduce chronic pain. Investigating the mechanisms of rTMS analgesia holds the potential to improve treatment efficacy. Using a double-blind and placebo-controlled design at both stimulation and pharmacologic ends, this study investigated the opioidergic mechanisms of rTMS analgesia by abolishing and recovering analgesia in 2 separate stages across brain regions and TMS doses. A group of 45 healthy participants were equally randomized to the primary motor cortex (M1), the dorsolateral prefrontal cortex (DLPFC), and the Sham group. In each session, participants received an intravenous infusion of naloxone or saline before the first rTMS session. Participants then received a second dose of rTMS session after the drugs were metabolized at 90 minutes. M1-rTMS-induced analgesia was abolished by naloxone compared with saline and was recovered by the second rTMS run when naloxone was metabolized. In the DLPFC, double but not the first TMS session induced significant pain reduction in the saline condition, resulting in less pain compared with the naloxone condition. In addition, TMS over the M1 or DLPFC selectively increased plasma concentrations of ß-endorphin or encephalin, respectively. Overall, we present causal evidence that opioidergic mechanisms are involved in both M1-induced and DLPFC-rTMS-induced analgesia; however, these are shaped by rTMS dosage and the release of different endogenous opioids.

Comparisons of Accelerated Continuous and Intermittent Theta Burst Stimulation for Treatment-Resistant Depression and Suicidal Ideation.

BACKGROUND: Suicidal ideation is a substantial clinical challenge in treatment-resistant depression (TRD). Recent work demonstrated promising antidepressant effects in TRD patients with no or mild suicidal ideation using a specific protocol termed intermittent theta burst stimulation (iTBS). Here, we examined the clinical effects of accelerated schedules of iTBS and continuous TBS (cTBS) in patients with moderate to severe suicidal ideation. METHODS: Patients with TRD and moderate to severe suicidal ideation (n = 44) were randomly assigned to receive accelerated iTBS or cTBS treatment. Treatments were delivered in 10 daily TBS sessions (1800 pulses/session) for 5 consecutive days (total of 90,000 pulses). Neuronavigation was employed to target accelerated iTBS and cTBS to the left and right dorsolateral prefrontal cortex (DLPFC), respectively. Clinical outcomes were evaluated in a 4-week follow-up period. RESULTS: Accelerated cTBS was superior to iTBS in the management of suicidal ideation (pweek 1 = .027) and anxiety symptoms (pweek 1 = .01). Accelerated iTBS and cTBS were comparable in antidepressant effects (p < .001; accelerated cTBS: mean change at weeks 1, 3, 5 = 49.55%, 54.99%, 53.11%; accelerated iTBS: mean change at weeks 1, 3, 5 = 44.52%, 48.04%, 51.74%). No serious adverse events occurred during the trial. One patient withdrew due to hypomania. The most common adverse event was discomfort at the treatment site (22.73% in both groups). CONCLUSIONS: These findings provide the first evidence that accelerated schedules of left DLPFC iTBS and right DLPFC cTBS are comparably effective in managing antidepressant symptoms and indicate that right DLPFC cTBS is potentially superior in reducing suicidal ideation and anxiety symptoms.

Functional dysconnectivity in youth depression: Systematic review, meta-analysis, and network-based integration.

Youth depression has been associated with heterogenous patterns of aberrant brain connectivity. To make sense of these divergent findings, we conducted a systematic review encompassing 19 resting-state fMRI seed-to-whole-brain studies (1400 participants, comprising 795 youths with major depression and 605 matched healthy controls). We incorporated separate meta-analyses of connectivity abnormalities across the levels of the most commonly seeded brain networks (default-mode and limbic networks) and, based on recent additions to the literature, an updated meta-analysis of amygdala dysconnectivity in youth depression. Our findings indicated broad and distributed findings at an anatomical level, which could not be captured by conventional meta-analyses in terms of spatial convergence. However, we were able to parse the complexity of region-to-region dysconnectivity by considering constituent regions as components of distributed canonical brain networks. This integration revealed dysconnectivity centred on central executive, default mode, salience, and limbic networks, converging with findings from the adult depression literature and suggesting similar neurobiological underpinnings of youth and adult depression.

Analgesic efficacy of theta-burst stimulation for postoperative pain.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) may be a relevant method to assist postoperative pain. However, studies to date have only used conventional 10 Hz rTMS and targeted the DLPFC for postoperative pain. A more recent form of rTMS, termed intermittent Theta Burst Stimulation (iTBS), enables to increase cortical excitability in a short period of time. This preliminary double-blind, randomised, sham controlled study was designed to evaluate the efficacy of iTBS in postoperative care across two distinct stimulation targets. METHODS: A group of 45 patients post laparoscopic surgery were randomised to receive a single session of iTBS over either the dorsolateral prefrontal cortex (DLPFC), primary motor cortex (M1), or Sham stimulation (1:1:1 ratio). Outcome measurements were number of pump attempts, total anaesthetic volume used, and self-rated pain experience, assessed at 1 hour, 6 hours, 24 hours, and 48 hours post stimulation. All randomised patients were analysed (n = 15 in each group). RESULTS: Compared to Sham stimulation, DLPFC-iTBS reduced pump attempts at 6 (DLPFC = 0.73 ± 0.88, Sham = 2.36 ± 1.65, P = 0.031), 24 (DLPFC = 1.40 ± 1.24, Sham = 5.03 ± 3.87, P = 0.008), and 48 (DLPFC = 1.47 ± 1.41, Sham = 5.87 ± 4.34, P = 0.014) hours post-surgery, whereby M1 stimulation had no effect. No group effect was observed on total anaesthetics, which was mainly provided through the continuous administration of opioids at a set speed for each group. There was also no group or interaction effect on pain ratings. Pump attempts were positively associated with pain ratings in the DLPFC (r = 0.59, P = 0.02) and M1 (r = 0.56, P = 0.03) stimulation. CONCLUSIONS: Our findings show that iTBS to the DLPFC reduces pump attempts for additional anaesthetics following a laparoscopic surgery. However, reduced pump attempts by DLPFC stimulation did not translate into a significantly smaller volume of total anaesthetic, due to the continuous administration of opioids at a set speed for each group. SIGNIFICANCE: Our findings therefore provide preliminary evidence for iTBS targeting the DLPFC to be used to improve postoperative pain management.

Personalized brain stimulation of memory networks.

BACKGROUND: The finding that transcranial magnetic stimulation (TMS) can enhance memory performance via stimulation of parietal sites within the Cortical-Hippocampal Network counts as one of the most exciting findings in this field in the past decade. However, the first independent effort aiming to fully replicate this finding found no discernible influence of TMS on memory performance. OBJECTIVE: We examined whether this might relate to interindividual spatial variation in brain connectivity architecture, and the capacity of personalisation methodologies to overcome the noise inherent across independent scanners and cohorts. METHODS: We implemented recently detailed personalisation methodology to retrospectively compute individual-specific parietal targets and then examined relation to TMS outcomes. RESULTS: Closer proximity between actual and novel fMRI-personalized targets associated with greater improvement in memory performance. CONCLUSION: These findings demonstrate the potential importance of aligning brain stimulation targets according to individual-specific differences in brain connectivity, and extend upon recent findings in prefrontal cortex.

Single-Pulse Transcranial Magnetic Stimulation-Evoked Potential Amplitudes and Latencies in the Motor and Dorsolateral Prefrontal Cortex among Young, Older Healthy Participants, and Schizophrenia Patients.

BACKGROUND: The combination of transcranial magnetic stimulation (TMS) with electroencephalography (EEG) allows for non-invasive investigation of cortical response and connectivity in human cortex. This study aimed to examine the amplitudes and latencies of each TMS-evoked potential (TEP) component induced by single-pulse TMS (spTMS) to the left motor (M1) and dorsolateral prefrontal cortex (DLPFC) among healthy young participants (YNG), older participants (OLD), and patients with schizophrenia (SCZ). METHODS: We compared the spatiotemporal characteristics of TEPs induced by spTMS among the groups. RESULTS: Compared to YNG, M1-spTMS induced lower amplitudes of N45 and P180 in OLD and a lower amplitude of P180 in SCZ, whereas the DLPFC-spTMS induced a lower N45 in OLD. Further, OLD demonstrated latency delays in P60 after M1-spTMS and in N45-P60 over the right central region after left DLPFC-spTMS, whereas SCZ demonstrated latency delays in N45-P60 over the midline and right central regions after DLPFC-spTMS. CONCLUSIONS: These findings suggest that inhibitory and excitatory mechanisms mediating TEPs may be altered in OLD and SCZ. The amplitude and latency changes of TEPs with spTMS may reflect underlying neurophysiological changes in OLD and SCZ, respectively. The spTMS administered to M1 and the DLPFC can probe cortical functions by examining TEPs. Thus, TMS-EEG can be used to study changes in cortical connectivity and signal propagation from healthy to pathological brains.

Using Brain Imaging to Improve Spatial Targeting of Transcranial Magnetic Stimulation for Depression.

Transcranial magnetic stimulation (TMS) is an effective treatment for depression but is limited in that the optimal therapeutic target remains unknown. Early TMS trials lacked a focal target and thus positioned the TMS coil over the prefrontal cortex using scalp measurements. Over time, it became clear that this method leads to variation in the stimulation site and that this could contribute to heterogeneity in antidepressant response. Newer methods allow for precise positioning of the TMS coil over a specific brain location, but leveraging these precise methods requires a more precise therapeutic target. We review how neuroimaging is being used to identify a more focal therapeutic target for depression. We highlight recent studies showing that more effective TMS targets in the frontal cortex are functionally connected to deep limbic regions such as the subgenual cingulate cortex. We review how connectivity might be used to identify an optimal TMS target for use in all patients and potentially even a personalized target for each individual patient. We address the clinical implications of this emerging field and highlight critical questions for future research.

High-frequency rTMS over the dorsolateral prefrontal cortex on chronic and provoked pain: A systematic review and meta-analysis.

BACKGROUND: High-frequency rTMS over the dorsolateral prefrontal cortex (DLPFC) has demonstrated mixed effects on chronic and provoked pain. OBJECTIVES/METHODS: In this study, a meta-analysis was conducted to characterise the potential analgesic effects of high-frequency rTMS over the DLPFC on both chronic and provoked pain. RESULTS: A total of 626 studies were identified in a systematic search. Twenty-six eligible studies were included for the quantitative review, among which 17 modulated chronic pain and the remaining investigated the influence on provoked pain. The left side DLPFC was uniformly targeted in the chronic pain studies. While our data identified no overall effect of TMS across chronic pain conditions, there was a significant short-term analgesia in neuropathic pain conditions only (SMD = -0.87). In terms of long-lasting analgesia, there was an overall pain reduction in the midterm (SMD = -0.53, 24.6 days average) and long term (SMD = -0.63, 3 months average) post DLPFC stimulation, although these effects were not observed within specific chronic pain conditions. Surprisingly, the number of sessions was demonstrated to have no impact on rTMS analgesia. In the analysis of provoked pain, our data also indicated a significant analgesic effect following HF-rTMS over the DLPFC (SMD = -0.73). Importantly, we identified a publication bias in the studies of provoked pain but not for chronic pain conditions. CONCLUSIONS: Overall, our findings support that HF-DLPFC stimulation is able to induce an analgesic effect in chronic pain and in response to provoked pain. These results highlight the potential of DLPFC-rTMS in the management of certain chronic pain conditions and future directions are discussed to enhance the potential long-term analgesic effects.